Process for Preparing Pyrrole Derivatives and Intermediates

ABSTRACT

The present invention relates to a process for preparing pyrrole derivatives of a class that is effective at inhibiting the biosynthesis of cholesterol in humans, and more particularly to improved synthetic methods for preparing 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids from 1,4-diketo starting materials. The invention further relates to intermediates in this process formula (I).

The present invention relates to a process for preparing pyrrolederivatives of a class that is effective at inhibiting the biosynthesisof cholesterol in humans, and more particularly to improved syntheticmethods for preparing 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids from1,4-diketo starting materials. The invention further relates tointermediates in this process.

It is known that certain 3,5-dihydroxy heptanoic acid derivatives arecompetitive inhibitors of the 3-hydroxy-3-methyl-glutaryl-coenzyme A(“HMG-CoA”). HMG-CoA is a key enzyme in the biosynthesis of cholesterolin humans. Its inhibition leads to a reduction in the rate ofbiosynthesis of cholesterol. The first HMG-CoA inhibitor to be describedis compactin([1S-[1α(R*),7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8a-hexahydro-7-methyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl2-methylbutanoate), which was isolated from cultures of Penicillium in1976. In 1987, lovastatin([1S-[1α(R*),3α,7β,8β(2S*,4S*),8αβ]]-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl2-methylbutanoiate) became the first HMG-CoA reductase inhibitorapproved by the Food and Drug Administration (FDA) for treatment ofhypercholesterolemia. Both compactin and lovastatin are derived frombacterial cultures. Two other naturally-derived HMG-CoA reductaseinhibitors, simvastatin and pravastatin are structurally related tocompactin and lovastatin.

In 1987, it was reported in U.S. Pat. No. 4,681,893 that compoundswithin a certain class of 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acid(and the corresponding lactones) also were effective at inhibiting theHMG-CoA reductase enzyme. One such compound is[R(R*,R*)]-2-(4-fluorophenyl)-β,δ-dihydroxy-5-(1-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1H-pyrrole-1-heptanoicacid (“atorvastatin”), which was said to provide surprising inhibitionin U.S. Pat. No. 5,273,995. Atorvastatin later received FDA approval asan adjunct to a low cholesterol diet to reduce elevated levels of totalcholesterol, low density lipoprotein cholesterol, apo B andtriglycerides and to increase levels of high density lipoproteincholesterol in patients with hyperlipidemia.

In contrast to compactin, lovastatin, simvastatin and pravastatin, thereis no known fermentation culture that produces atorvastatin. It, andother 3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids, must be synthesizedby traditional synthetic methods.

A number of processes for the synthesis of 3,5-trihydroxy-7-pyrrol-1-ylheptanoic acids and in particular atorvastatin are known. Some of theprocesses are concerned with the synthesis of the 3,5-dihydroxyheptanoic acid side chain of the pyrrole ring while others are concernedwith the formation of the pyrrole ring.

For example, EP-A-0 330 172 teaches that the pyrrole ring can be formedby the Paal-Knorr reaction between an 1,4-diketone and a primary aminebeing a precursor of the 3,5-dihydroxy heptanoic acid side chain. The1,4-diketone already bears those substituents required at the pyrrolering of atorvastatin and in particular the (phenylamino)carbonyl grouprequired at position 4 of the pyrrole ring.

WO 2004/046105 also discloses a process comprising the Paal-Knorrreaction between a ketal-protected 7-amino-3,5-dihydroxy-1-heptanol andan 1,4-diketone. Also this diketone already comprises the aminocarbonylfunctionality required at position 4 of the pyrrole ring inatorvastatin.

Similar reactions are disclosed in EP-A-0 687 263, WO 02/057274 and WO03/004457. All these synthesis routes have in common that the Paal-Knorrreaction is conducted with an 1,4-diketone comprising an amino carbonylmoiety and in particular (phenylamino)carbonyl at the position requiredto finally obtain atorvastatin.

It is, however, difficult to obtain the required 1,4-diketone comprisingthe amino carbonyl moiety in good yield and purity. Moreover, even whenstarting from a commercially available 1,4-diketone precursor comprisingthe required (phenylamino)carbonyl side chain, it turned out to bedifficult, if not impossible, to replace the phenylamino residue byother residues such as alkoxy or aryloxy residues without cleavage ofthe diketone. This limits the possible variation of the substituents andmakes a screening for new compounds for inhibiting the biosynthesis ofcholesterol in humans difficult.

Therefore, there is still a need for further methods of synthesizingpyrrole derivatives and in particular 3,5-dihydroxy-7-pyrrol-1-ylheptanoic acids having HMG-CoA inhibitory activity.

1,3-dipolar cycloaddition reactions of mesoionic munchnone(1,3-oxazolium-5-olate) with ethyl phenylpropiolate andN1,3-diphenyl-2-propynamide are described by P. S. Pandey et al., inBioorganic & Medicinal Chemistry Letters 14 (2004) 129-131. The reactionof mesoionic munchnone with ethyl phenylpropiolate is found to beregioselective giving 1:9 ratio of regioisomers 8a and 8b

This reaction is, however, said to be undesirable, because 8a is thedesired isomer for preparing atorvastatin. The document thereforesuggests to carry out the reaction of the mesoionic munchnone withN1,3-diphenyl-2-propionamide, because this reaction is notregioselective and, thus, gives a higher yield of the desired isomer.

Thus, an object of the present invention is to provide a further processfor preparing pyrrole derivatives and in particular3,5-dihydroxy-7-pyrrol-1-yl heptanoic acids. The intermediates in theprocess should be obtainable in good yield and purity. Moreover, theprocess should be suitable for an industrial scale. Furthermore, theprocess and the intermediates should provide the option to easily modifythe side chain on the carbonyl substituent at position 4 of the pyrrolering of atorvastatin to make the screening of compounds bearingdifferent substituents easier.

It has now surprisingly been found that the above problems can beovercome by a process for preparing a pyrrole derivative of the formulaI

whereinR¹ is hydrogen or a straight or branched, saturated or unsaturated C₁₋₃₀hydrocarbon group which may comprise 1-5 oxygen atoms, 1-5 nitrogenatoms, 1-2 sulfur atoms, 1 selenium atom and/or 1-5 —NR⁶— residues,which hydrocarbon group may be substituted with 1-5 optionally protectedhydroxy groups, 1-5 —OR⁷ residues, 1-5 —NR⁸R⁹ residues, 1-5 halogenatoms and/or 1-5 optionally protected carboxy groups, in whichhydrocarbon group 1-5 carbon atoms may form carbonyl groups and whichhydrocarbon group or part of which hydrocarbon group may form one ormore rings (such as lactones, lactames or oxazolidines),R² is —OR³, —NR⁴R⁵, —NR¹⁰NR¹¹R¹², —NR¹³OR¹⁴, —ONR¹⁵R¹⁶ or halogen,R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ and R¹⁶ areindependently selected from hydrogen or a straight, branched and/orcyclic, saturated or unsaturated C₁₋₁₀ alkyl residue or aryl residue,both residues being optionally substituted with 1-3 optionally protectedhydroxy or carboxy groups, 1-3 —OR⁷ residues, 1-3 —NR⁸R⁹ residues and/or1-3 halogen atoms, the C₁₋₁₀ alkyl residue optionally comprising 1-3oxygen atoms, 1-3 nitrogen atoms and/or 1-3 —NR⁶— residues, the C₁₋₁₀alkyl residue further optionally comprising or being substituted with 1or 2 aryl residues,or a salt thereof,which process comprises the steps of reacting a compound of the formulaII

wherein R² is defined as above, or a salt thereof with a compound of theformulae IIIa, IIIb or IIIc

R¹—NH₂  IIIa,

R¹—NH—COO⁻H₃N⁺—R¹  IIIb,

R¹—NH—SiR¹⁷R¹⁸R¹⁹  IIIc,

or mixtures thereof, wherein R¹ is defined as above,R¹⁷ and R¹⁸ are independently selected from straight, branched and/orcyclic C₁₋₁₀ alkyl residues or aryl residues, andR¹⁹ is straight, branched and/or cyclic C₁₋₁₀ alkyl residue, arylresidue or —NH—R¹,and, if necessary, converting the obtained pyrrole derivative having thesubstituent R¹ into a pyrrole derivative having a different substituentR¹,provided that if R² is —NR⁴R⁵ the compound of the formula IIIa is NH₃.

Preferably the compound of the formula IIIa is not

wherein X¹, X² and X³ are hydrogen or protecting groups, in particularif R² is —OR³ (such as —OCH₂CH₃).

One advantage of the process of the present invention is that if R² is—OR³ or halogen the compound of the formula II is easy to produce ingood yield and purity. A further advantage is that if R² is —OR³ orhalogen the intermediate compound of the formula II provides thepossibility of easy substitution of the R² residue, thereby providinghigher flexibility for example for screening substituted pyrrolecompounds for their pharmaceutical activity. This finding isparticularly unexpected, since the corresponding known diketone anilide(2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide) turned out to be stable to hydrolysis. It reacts withbase and hydrogen peroxide not to the expected acid but it breaks to1-(4-fluorophenyl)-2-phenylethan-1-one (compound of formula VIII). Thisproblem does not arise when using the corresponding diketone ester oracid halogenide (compound of the formula II).

Moreover, if using NH₃ as the compound of the formula IIIa in theprocess of the present invention, the yield of the ring-forming reactionis significantly higher compared to reactions with compounds of theformula IIIa, wherein R¹ is other than hydrogen.

In the process of the present invention a compound of the above formulaII is reacted with a compound of the above formulae IIIa, IIIb or IIIc.In the compound of the formulae IIIa, IIIb and IIIc R¹ is eitherhydrogen or a hydrocarbon group. If in the compound of formula IIIa R¹is hydrogen, liquid ammonia, aqueous ammonia or a solution of anammonium salt such as NH₄C₁ or CH₃COONH₄ can be used. Thus, NH₃ as onecompound of the formula IIIa also includes NH₄ ⁺ ions which will alwaysbe present in the reaction solution in dependence of the pH value of thesolution. Preferably the diketone of the formula II is reacted withCH₃COONH₄. The reaction can be carried out in any common inert solventsuch as THF preferably at elevated temperatures, such as, for example,under reflux.

In one embodiment the reaction is conducted with ammonium acetate inrefluxing THF for about 6 hours. The yield of this reaction isconsiderably higher than the yield of the similar reaction withbenzylamine instead of ammonium acetate.

Instead of NH₃ a primary amine (formula IIIa), an amine derivative withcarbon dioxide (formula IIIb) or a silylated amine (formula IIIc) can beemployed in the process of the present invention. In this case thesubstituent R¹ is not particularly limited and can be chosen among thehydrocarbon groups defined above for R¹. Preferably R¹ is a straight orbranched, saturated or unsaturated C₁₋₂₀ hydrocarbon group, inparticular C₁₋₂₀ alkyl group, which may comprise 1-5 oxygen atoms, maybe substituted with 1-5 optionally protected hydroxy groups, 1 or 2—NR⁸R⁹ residues (wherein R⁸ and R⁹ are defined as above) and/or 1 or 2optionally protected carboxy groups, in which hydrocarbon group 1-5carbon atoms may form carbonyl groups and which hydrocarbon group orpart of which hydrocarbon group may form 1 or more rings.

In one embodiment of the process of the present invention R¹ is aresidue of the formula X

which may optionally be protected or is chosen such that it can easilybe converted into a residue of the formula X. Residues which can beconverted into residues of the formula X are for example known from WO2004/046105, WO 94/20492, WO 02/057274, WO 02/055519, EP-A-0 330 172,EP-A-0 179 559, EP-A-0 247 633 and EP-A-0 409 281. The disclosures ofthese documents are therefore incorporated by reference herein.

Preferred residues for R¹ are selected from the following residues:

wherein R^(a) is —OR^(b), —SR^(c), SeR^(d) or —NR^(e)R^(f);R^(b), R^(c) and R^(d) are independently selected from straight,branched and/or cyclic, saturated or unsaturated C₁₋₁₀ alkyl residue,aryl residue or arylalkyl residue;R^(e) and R^(f) are independently selected from straight, branchedand/or cyclic, saturated or unsaturated C₁₋₁₀ alkyl residue, arylresidue or arylalkyl residue orR^(e) and R^(f) taken together are

—(CH₂)₄—

—(CH₂)₅—

—(CH(R^(g))—CH₂)₃—

—(CH(R^(g))—CH₂)₄—

—(CH(R^(g))—(CH₂)₂—CH(R^(g)))—

—(CH(R^(g))—(CH₂)₃—CH(R^(g)))—

—CH₂—CH₂-A-CH₂—CH₂—

—CH(R^(g))—CH₂-A-CH₂—CH₂—

—CH(R^(g))—CH₂-A-CH₂—CH(R^(g))—,

wherein R^(g) is C₁₋₄ alkyl residue and A is O, S or NR^(h), whereinR^(h) is hydrogen or C₁₋₄ alkyl residue;and each hydroxy group may independently be protected with a suitableprotecting group whereby two hydroxy groups together with theirprotecting group may form a ring. It is understood that any of theresidues R¹ can be, if possible, in its lactone or lactame form.

As protecting groups for the optionally protected hydroxy groups and theoptionally protected carboxy groups usual protecting groups known to theperson skilled in the art may be used. Suitable protecting groups areexemplified in WO 03/044011, which therefore is incorporated byreference herein.

In the compound of the formula II R² may be —OR³, —NR⁴R⁵ or halogen,preferably —OR³ or halogen and most preferred —OR³. Herein R³, R⁴ and R⁵are defined as above.

For R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵, R¹⁶,R^(b), R^(c), R^(d), R^(e) and R^(f) the alkyl residue is preferably astraight or branched, saturated or unsaturated C₁₋₆ alkyl residue or acyclic C₃₋₆ alkyl residue, such as methyl, ethyl, n-propyl, iso-propyl,n-butyl, iso-butyl, tert-butyl, pentyl, n-hexyl or cyclohexyl. Preferredaryl residues are phenyl and naphthyl, particularly preferred phenyl.The aryl residue furthermore includes heteroaryl residues such aspyrrole or pyridine. The preferred arylalkyl residue is benzyl.

For R¹⁷, R¹⁸ and R¹⁹ the alkyl residue is preferably a straight orbranched C₁₋₆ alkyl residue or a cyclic C₃₋₆ residue, such as methyl,ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl,n-hexyl or cyclohexyl. Preferred aryl residues are phenyl and naphthyl,particularly preferred phenyl. The aryl residue furthermore includesheteroaryl residues such as pyrrole or pyridine.

In the present application halogen stands for fluoro, chloro, bromo oriodo, preferably chloro or bromo.

The primary amine of the formula IIIa or the amines of the formulae IIIbor IIIc are reacted with a diketone of the formula II. This reaction canfor example be carried out under the same conditions as described abovefor the reaction, wherein the compound of the formula IIIa is NH₃.Further detailed reaction conditions can for example be found in WO2004/046105, WO 94/20492 and EP-A-0 330 172. For example, the reactioncan be conducted under heating with azeotropical water removed in anappropriate solvent or mixture of solvents catalyzed with an acid, suchas, for example, pivalic acid. As suitable solvents n-heptane, tolueneand THF or mixtures thereof can be mentioned. Alternatively the reactioncan be conducted without any solvent (neat) under heating the reactantsto for example about 120° C. to 140° C.

When reacting a compound of the formula II, wherein R² is —OR³ orhalogen with a compound of the formulae IIIa, IIIb or IIIc a by-productof the following formula IV

wherein R¹ at both occurrences are identical and defined as above may beobtained. In this case the desired pyrrole derivative of the formula Imay be separated from the reaction by-product of the formula IV, and thereaction by-product can subsequently be converted into a pyrrolederivative of the formula I, wherein R² is —OR³, —NR⁴R⁵ or halogen andR³, R⁴ and R⁵ are defined as above, provided that —NR⁴R⁵ is differentfrom —NHR¹. This reaction route is effective for recycling undesiredby-products obtained in the reaction between the diketone of the formulaII and the amine of the formula III.

In a further embodiment of the process of the present invention thecompound of the formula II is obtained by

a) reacting a compound of the formula V

wherein R² is defined as in claim 1,with 4-fluorobenzaldehyde orb) reacting a compound of the formula VI

wherein Hal is halogen, preferably bromo with a compound of the formulaVII

wherein R² is defined as in claim 1 and M⁺ is selected from H⁺, Li⁺, Na⁺and K⁺, preferably Na⁺.

The above reaction route a) has the advantage that the compound of theformula V, wherein R² is —OR³ can be easily purified by distillation.Thus, this intermediate can be employed in the following reaction in ahighly pure form.

The above reaction route b) has the advantage that the compound of theformula VI can easily be obtained from the commercially available2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide by cleavage with hydrogen peroxide in the presence of abase such as NaOH.

Above reaction a) can for example be carried out under solvent-freeconditions catalyzed by 2-(2-hydroxyethyl)-3-methyl-4-ethylthiazoliumbromide in the presence of triethylamine under heating to for example toa temperature of about 60° C. to about 80° C.

In reaction route a) the compound of the formula V can be obtained byreacting a compound of the formula IX

wherein R² is defined as above with benzaldehyde. This reaction can becarried out in the presence of a catalyst such as, for example,piperidine and glacial acetic acid, ethylene diamine and glacial aceticacid, β-alanine and glacial acetic acid, and the like in an inertsolvent such as, for example, toluene, heptane, hexane, and the like forabout 24 to about 36 hours at about 60° C. to about 120° C. with theremoval of water to afford a compound of the formula V.

If in the compound of the formula V R² is —OR³, this compound isheat-stable and can be distilled as to separate the desired compound ofthe formula V from undesired by-products of the reaction. In a preferredembodiment of the process of the present invention the reaction betweenthe compound of the formula IX and benzaldehyde is catalyzed withβ-alanine in the presence of acetic acid, preferably glacial aceticacid, in toluene. The reaction mixture is heated under reflux withazeotropic removal of water for about 24 hours. After usual workup theproduct can be distilled under reduced pressure.

In the alternative embodiment according to above route b) the compoundof the formula II is obtained by reacting the compounds of the formulaVI and VII with each other. This addition reaction can be carried out inany suitable inert organic solvent, preferably anhydrous inert organicsolvent, such as, for example, ethers, e.g. diethyl ether,1,2-diethoxyethane, 1,2-dimethoxyethane, THF or mixtures thereof.Preferably the reaction is carried out in THF. The reaction temperaturemay be in the range of for example about 0° C. to about 40° C.,preferably from about 0° C. to about room temperature.

In a preferred embodiment the compound of the formula VII is prepared insitu.

The compound of the formula VI can be obtained by halogenating thecompound of the formula VIII

Halogenation, preferably bromination of the compound of the formula VIIIcan be carried out with for example bromine in an inert organic solvent,preferably an anhydrous inert organic solvent, such as, for example,halogenated lower alkane solvents, e.g. CCl₄, CHCl₃, 1,1-dichloroethane,1,2-dichloroethane, methylene chloride, 1,1,2-trichloroethane ormixtures thereof. A preferred solvent is CHCl₃. The reaction can becarried out for example at a temperature of about 0° C. to about 40° C.

The compound of the formula VIII can be obtained by cleavage of acompound of the formula II, wherein R² is —NR⁴R⁵, and R⁴ and R⁵ aredefined as above, such as the commercially available2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxo-pentanoicacid phenylamide. The cleavage can be carried out for example withhydrogen peroxide in the presence of a base such as NaOH.

A particularly advantageous route for the synthesis of a compound of theformula II is shown in the following scheme:

Advantages of the synthesis of diketone ethyl ester by this route are:

-   -   no need of reaction solvent in step 2 (environmental, economic);    -   no need of recrystallization process in step 1 (environmental,        economic), product is isolated by distillation;    -   this is the shortest synthetic route (only 2 steps) in        comparison with other known processes (3-5 steps required);    -   in the process for the step 1 nontoxic catalyst (β-alanine) is        used (environmental);    -   no need of toxic a corrosive reagents (like bromine in        alternative route);    -   all starting materials are commercially available.

The present invention further relates to compounds of the formula I, IIand IV, wherein R² is —OR³ or halogen and R¹ at both occurrences areidentical and defined as above, respectively. These compounds are usefulintermediates in the preparation of atorvastatin.

The present invention will now be further illustrated by the followingexamples which are not intended to be limiting.

EXAMPLES 1. Synthesis of ethyl-2-benzylidene-4-methyl-3-oxopentanoate(compound of formula V)

A mixture of benzaldehyde (33.8 g, 319 mmol), ethyl isobutyrylacetate(50.4 g, 319 mmol), β-alanine (1.0 g) and acetic acid (10 ml) in 600 mlof toluene was stirred and heated under reflux with azeotropic removalof water (Dean-Stark adapter) until GC analysis showed no presence ofstarting material (24 h). The solution was cooled, poured intoethylacetate (400 ml), washed with 1 M HCl solution (2×100 ml),saturated NaHCO₃ solution (2×100 ml) and brine (100 ml) and dried overanhydrous Na₂SO₄. The solvent was removed under reduced pressure toyield 76.3 g of brown oil which was further distilled under reducedpressure (bp 105-120° C./0.06 mm Hg) to afford 58.9 g (75%) of ethyl2-benzylidene-4-methyl-3-oxopentanoate as a mixture of isomers (major˜70%).

2. Synthesis of ethyl2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxopentanoate(compound of formula II)

To a stirred mixture of ethyl 2-benzylidene-4-methyl-3-oxopentanoate(52.5 g, 0.213 mol), 4-fluorobenzaldehyde (39.7 g, 0.320 mol) and2-(2-hydroxyethyl)-3-methyl-4-ethylthiazolium bromide (8.11 g, 0.032mol) was added dropwise triethylamine (21.3 ml). The solution turneddark and precipitation of solid particles was observed. A mixture wasthen heated at 70° C. until the reaction mixture did not containstarting ethyl 2-benzylidene-4-methyl-3-oxopentanoate (HPLC monitoring).After cooling to room temperature, the mixture was diluted withethylacetate (500 ml) and water (100 ml). The organic phase was washedwith 1 M HCl solution (2×100 ml), saturated NaHCO₃ solution (2×100 ml)and brine (100 ml) and dried over anhydrous Na₂SO₄. The solvent wasremoved under reduced pressure to yield 100.2 g of impure oily productwhich was then dissolved in dichloromethane (400 ml) and silicagel (50g) was added. The mixture was stirred for 10 minutes and the silicagelwas filtered off and washed with dichloromethane (500 ml). Air wasbubbled through the combined filtrates for 24 hours in order to oxidizeremaining 4-fluorobenzaldehyde. Additional 200 ml of dichloromethane wasadded to the reaction mixture to compensate losses due to evaporationand the solution was washed with saturated NaHCO₃ solution (2×100 ml)and water (100 ml) and dried over anhydrous Na₂SO₄. The solvent wasremoved under reduced pressure to yield 87 g yellow oily product whichslowly solidified. The oily product contains 85% of ethyl2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxopentanoate andthe calculated yield was then 94%.

3. Synthesis of ethyl5-(4-fluorophenyl)-2-isopropyl-1-phenethyl-4-phenyl-1H-pyrrole-3-carboxylate(compound of the formula I)

Ethyl2-[2-(4-fluorophenyl)-2-oxo-1-phenyl-ethyl]-4-methyl-3-oxopentanoate(reagent 1) was reacted with 2-phenylethylamine (reagent 2) under theconditions summarized in the following table 1.

TABLE 1 Ratio of Exp. reagents Reaction No.: 1:2:catalyst CatalystSolvents Conditions time [h] Yield [%] 1 1:1:1 Pivalic acid n-heptane,Reflux with 96 72.4 THF, azeotropic water toluene removal 2 1:1:2Pivalic acid — Heating neat at 48 65.0 125-130° C. 3 1:1.5:1.5 Pivalicacid n-heptane, Reflux with 24 68.5 THF, azeotropic water tolueneremoval

1. A process for preparing a pyrrole derivative of the formula I

wherein R¹ is hydrogen or a straight or branched, saturated orunsaturated C₁₋₃₀ hydrocarbon group which may comprise 1-5 oxygen atoms,1-5 nitrogen atoms, 1-2 sulfur atoms, 1 selenium atom and/or 1-5 —NR⁶—residues, which hydrocarbon group may be substituted with 1-5 optionallyprotected hydroxy groups, 1-5 —OR⁷ residues, 1-5 —NR⁸R⁹ residues, 1-5halogen atoms and/or 1-5 optionally protected carboxy groups, in whichhydrocarbon group 1-5 carbon atoms may form carbonyl groups and whichhydrocarbon group or part of which hydrocarbon group may form one ormore rings, R² is —OR³, —NR⁴R⁵, —NR¹⁰CONR¹¹R¹², —NR¹³OR¹⁴, —ONR¹⁵R¹⁶ orhalogen, R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, R¹⁵ andR¹⁶ are independently selected from hydrogen or a straight, branchedand/or cyclic, saturated or unsaturated C₁₋₁₀ alkyl residue or arylresidue, both residues being optionally substituted with 1-3 optionallyprotected hydroxy or carboxy groups, 1-3 —OR⁷ residues, 1-3 —NR⁸R⁹residues and/or 1-3 halogen atoms, the C₁₋₁₀ alkyl residue optionallycomprising 1-3 oxygen atoms, 1-3 nitrogen atoms and/or 1-3 —NR⁶—residues, the C₁₋₁₀ alkyl residue further optionally comprising or beingsubstituted with 1 or 2 aryl residues, or a salt thereof, which processcomprises the steps of reacting a compound of the formula II

wherein R² is defined as above, or a salt thereof, with a compound ofthe formulae IIIa, IIIb or IIIcR¹—NH₂  IIIa,R¹—NH—COO⁻H₃N⁺—R¹  IIIbR¹—NH—SiR¹⁷R¹⁸R¹⁹  IIIc, or mixtures thereof, wherein R¹ is defined asabove, R¹⁷ and R¹⁸ are independently selected from straight, branchedand/or cyclic C₁₋₁₀ alkyl residue or aryl residue; and R¹⁹ is straight,branched and/or cyclic C₁₋₁₀ alkyl residue, aryl residue or —NH—R¹, and,if necessary, converting the obtained pyrrole derivative having thesubstituent R¹ into a pyrrole derivative having a different substituentR¹, provided that if R² is —NR⁴R⁵ the compound of the formula IIIa isNH₃.
 2. The process according to claim 1, wherein R² is —OR³ or halogen.3. The process according to claim 2, which comprises the additional stepof separating the pyrrole derivative of the formula I from the reactionby-product of the formula IV

wherein R¹ at both occurrences are identical and defined as in claim 1.4. The process according to claim 3, which comprises the additional stepof converting the separated reaction by-product of the formula IV into apyrrole derivative of the formula I, wherein R² is —OR³, —NR⁴R⁵ orhalogen and R³, R⁴ and R⁵ are defined as in claim 1, provided that—NR⁴R⁵ is different from —NHR¹.
 5. The process according to claim 1,wherein the compound of formula II is obtained by a) reacting a compoundof the formula V

wherein R² is defined as in claim 1, with 4-fluorobenzaldehyde or b)reacting a compound of the formula VI

wherein Hal is halogen, with a compound of the formula VII

wherein R² is defined as in claim 1 and M⁺ is selected from H⁺, Li⁺, Na⁺and K⁺, preferably Na⁺.
 6. The process according to claim 5, wherein thecompound of the formula VI is obtained by halogenating the compound ofthe formula VIII


7. The process according to claim 6, wherein the compound of the formulaVIII is obtained by cleavage of a compound of the formula II, wherein R²is —NR⁴R⁵, and R⁴ and R⁵ are defined as in claim
 1. 8. The processaccording to claim 5, wherein the compound of the formula V is obtainedby reacting a compound of the formula IX

wherein R² is defined as in claim 1 with benzaldehyde.
 9. The processaccording to claim 1, wherein R¹ is a straight or branched, saturated orunsaturated C₁₋₂₀ hydrocarbon group which may comprise 1-5 oxygen atoms,may be substituted with 1-5 optionally protected hydroxy groups, 1 or 2—NR⁸R⁹ residues (wherein R⁸ and R⁹ are defined as in claim 1) and/or 1or 2 optionally protected carboxy groups, in which hydrocarbon group 1-5carbon atoms may form carbonyl groups and which hydrocarbon group orpart of which hydrocarbon group may form one or more rings.
 10. Theprocess according to claim 1, wherein R³, R⁴, R⁵, R⁶, R⁷, R⁸ and R⁹ areindependently selected from hydrogen, a straight or branched, saturatedor unsaturated C₁₋₆ alkyl residue, a cyclic C₃₋₆ alkyl residue orphenyl.
 11. The process according to claim 1, wherein in the compound ofthe formula I R² is or is converted to —NH-phenyl and R¹ is or isconverted to a residue of the formula X

which may optionally be protected.
 12. A compound of the formula I

wherein R² is —OR³ or halogen and R¹ and R³ are defined as in claim 1,or a salt thereof, provided that if R³ is ethyl R¹ is not —CH₂-phenyl.13. A compound of the formula II

wherein R² is —OR³ or halogen and R³ is defined as in claim 1, or a saltthereof, provided that R³ is not ethyl.
 14. A compound of the formula IV

wherein R¹ at both occurrences are identical and defined as in claim 1,or a salt thereof.
 15. A method of preparing atorvastatin comprising thestep of using a compound of the formula I as defined in claim 12 for thepreparation thereof.
 16. A method of preparing atorvastatin comprisingthe step of using a compound of the formula II as defined in claim 13for the preparation thereof.
 17. A method of preparing atorvastatincomprising the step of using a compound of the formula IV as defined inclaim 14 for the preparation thereof.